P3‐222: Genetic regulation of Aβ levels in human plasma

Amyloid β protein (Aβ) ending at amino acid 40 (Aβ40) and 42 (Aβ42) accumulates in human brain with aging and as a defining pathological component in Alzheimer's disease (AD). Plasma Aβ has been suggested as a marker of AD susceptibility, diagnosis and treatment effects. Moreover, clear heritability of plasma Aβ levels has been shown in late onset AD pedigrees, supporting the importance of genes in plasma Aβ regulation. In our study we aim to identify genetic factors involved in the regulation of Aβ levels in human plasma. In this study we investigated 1282 individuals within the Uppsala Longitudinal Study of Adult Men (ULSAM). ELISA measurements of Aβ40 and Aβ42 were performed in more than 2400 plasma samples collected at the 70, 77 and 82 year follow-ups. In addition, over 1100 DNA samples from ULSAM participants have been genotyped for 3 118 SNP's in 370 candidate genes for common diseases. Using UNPHASED software we have performed association analysis between quantitative measures of Aβ and genetic variants. We have performed association analyses between SNP's and Aβ40 and Aβ42 levels at age 70, 77 and 82. We have also performed association analysis between SNP's and averaged Aβ40 and Aβ42 levels from two or three time points. Over 70 genes showed association with levels of Aβ40 or Aβ42 at individual time points. Average levels of Aβ40 were associated with polymorphisms in 16 genes and average levels of Aβ42 were associated with polymorphisms in 13 genes (p < 0.05). However, only six genes showed association with both Aβ40 and Aβ42. Interestingly, carriers of the known AD susceptibility gene APOE ϵ4 allele have lower Aβ40 and Aβ42 levels in plasma, as compared to individuals without the ϵ4 allele. These results support a genetic component to plasma amyloid beta protein levels that may also reflect AD risk.